Viral and microbial pathogens transmitted through or originating from exposure of the urogenital or anorectal epithelium or mucosa are a major problem in medicine. Urogenital and anorectal structures and systemic tissues beyond may be affected. Such infectious disease can result from mucosal exposure during sexual contact or other contact or from opportunistic growth of the urogenital or anorectal flora.
A tendency for recurrence, reinfection and chronic progression is characteristic of many urogenital or anorectal tract infections. Viral or microbial adherence to the mucosal epithelium is frequently a key precondition for the colonization or infection of these tissues. In-vitro studies have shown that the adherence phenomenon is often accomplished via the pili of bacteria or other outer membrane constituents of infecting viruses or microbes. Such adherence can be prevented by the development of antibodies and/or enhancement of cell-mediated immunity against antigenic components of the invading organisms, which include viruses, bacteria, protozoa, fungi and the like.
Bacteria and viruses are the most frequent causative agents of genitourinary or anorectal tract infections. The genitourinary/anorectal tracts can also be infected by other microorganisms, such as protozoa, fungi and the like. Recurrence and chronicity are characteristic of many genintourinary/anorectal tract infections. Recurrence may be due to either relapse or reinfection.
In spite of a great deal of progress in the treatment of infectious disease, the morbidity and mortality of genitourinary/anorectal tract infections remains unchanged. The reasons for this are myriad and depend on the host susceptibility, heightened sexual exposure and on viral or microbial factors.
Recurrences of infections with a previously infecting organism may result from inadequacy of the treatment administered because of incorrect choice of medicine, emergence of resistance strains, insufficient treatment duration, insufficient concentration of chemotherapeutic agents, the existence of bacterial L-forms, and persistence or survival of viral or microbes in urinary calculi or epithelium of the vaginal or anorectal mucosa and surrounding tissues. Recurrent urogenital/anorectal infections can be reinfections with different strains of organisms responsible for prior infections and generally having a greater capacity to adhere to the epithelial cells of the vagina, urethra or rectum. The reinfecting bacteria can originate in the intestinal flora. Frequently, viruses and chlamydia pathogens may lay dormant in epithelial cells and revert to an active state through mechanisms not fully understood.
The composition of the urogenital or anorectal flora may be altered by chemotherapeutic agents that are used in the treatment and prophylaxis of genitourinary or intestinal infections. The flora frequently develop antibiotic resistance and cause a reinfection or primary opportunistic infection. Such infections may be a consequence of the eradication of normal, harmless flora, such as lactobacilli, allowing other pathogenic microbes, resistant to the antibiotics, to flourish.
Studies have revealed that low levels of secretory IgA (sIgA) in urine indicate a defective local immune response of the urinary tract and favor urogenital tract infections. An important property of sIgA is the prevention of interaction of bacterial pili or outer membrane constituents of viruses or other microbes with the specific receptors found on the epithelium of the vaginal/anorectal mucosa or urinary tract. Pili-mediated adhesiveness is an important virulence factor of the bacteria involved. In the case of viruses and non-piliated microbes, other outer membrane constituents are involved in host-attachment phenomena, prior to propagation to infection. For the defense against infection it is important to reduce the adhesion of the pathogens to the epithelium or to prevent the attachment of the pathogen altogether.
Normally, the host organism forms specific local antibodies against the invading bacteria and secretes these antibodies as sIgA. In patients with persisting or frequently relapsing urinary tract infections this natural mechanism of local immunological infection defense is apparently disturbed. Therefore, enhancement of immune defense is a rational means of eliminating the cause of recurrent urinary tract infections.
A vaccination strategy that stimulates the production of antibodies to a spectrum of antigens that are present in several types of pathogens is desirable. Vaccination of the urogenital or anorectal epithelium with nucleic acids encoding specific proteins involved in pathogen-host attachment phenomena presents a novel method of stimulating cell-mediated immunity.
Previously, vaccines against urogenital infections have been administered parenterally or orally and have resulted in enhanced resistance to urogenital infections. However, patients suffer from side effects such as malaise, fever, and muscle soreness. Oral vaccines are subject to the destructive influences of gastric acidity and digestive enzymes. A necessary retention at a local surface for extended transmucosal contact may be difficult to achieve. Prior art concerning mucosal vaccination through the vaginal route using whole cell lysates has taught enhanced resistance to recurrent infection, but there is no mention of transmucosal immunization by the anorectal route and the production of transmucosal immunity against local infection at the site of delivery system target. No specifically therapeutic local immune response to a delivery system is presented. The efficacy presented is confined to non-specific vaccine materials that present a complex potential to produce complex reactions by poorly understood mechanisms.
In an attempt to overcome the defects associated with parenteral and oral administrations of vaccines or in using vaginally-delivered vaccines comprised of fractionated or whole cell extracts, an intravaginal or intrarectal mucosal vaccine delivery system against infections is proposed wherein the vaccine is comprised of purified antigenic determinants capable of stimulating an immune response to pathogenic factors involved in attachment and disease. Administering a vaccine against urogenital or anorectal infections intravaginally or intrarectally is that there is a mucosal immune system wherein antigens are absorbed through mucosal surfaces and processed by specialized local lymphoid tissues, after which antibodies are secreted onto local mucosal surfaces. In the case of nucleotide vaccines, epithelial cells of the mucosa express the proteins to the cell surface promoting cellular-mediated immune responses. As discussed above, in the genitourinary tract, temporary or partial deficiencies in local vaginal or urinary antibodies are an important factor in the heightened susceptibility to urogenital infections shown in some women. Immunization via the mucosal surfaces within the genitourinary tract is preferable to parental or oral routes as it has been discovered that vaccination via the intravaginal surface creates a secretory immune response in the urogenital tract. With nucleotide vaccines, such vaccination stimulates specific cellular-mediated immune responses.
Advances in the identification of specific pathogenic factors involved in infection attachment and propagation, the elucidation of the mucosal immune system and the ability of the mucosal tissue to participate in cellular-mediated immune response via nucleotide vaccination suggest that vaccination of the genitourinary/anorectal tract by a transvaginal or anal route is preferable to oral or parenteral immunization. The specific method of vaginal or rectal immunization may actually resolve infection before disease ensues, preventing pathogen attachment or neutralizing toxins prior to pathogen and host interaction.
For instance, in the past, urinary tract infections vaccines were administered vaginally in the form of a liquid vaccine. Several problems were associated with the intravaginal administration of liquid urinary tract infections vaccine. The major problem encountered was that the liquid vaccine flowed out of the vagina soon after insertion. This severely limits the amount of time that the liquid antigens are in contact with the mucosal surface of the vagina, decreasing the effectiveness of the vaccine. The antigens need sufficient contact with the vaginal mucous membrane to elicit a secretory immunoglobin response. Patients receiving the vaccination were required to lie in a supine position for an extended time after receiving the vaccine to prevent the vaccine from immediately flowing out of the vagina. However, often the vaccine still leaked out of the vagina following the period of time in the supine position, limiting the effectiveness of the vaccine. In addition, the requirement that patients lie in a supine position for an extended time after receiving the vaccine, is a burden on the patient. Patients may receive several vaccinations over the course of treatment and the patients must spend a considerable amount of time after each vaccination immobile.
U.S. Ser. No. 08/923,813 entitled Vaginal Suppository Vaccine For Urogenital Infections was filed Sep. 4, 1997 and allowed. This application is owned by assignee herein and relates to a suppository based vaccine delivery system for immunizing against urogenital infectious diseases in humans.
It is apparent that improvements are necessary in optimizing vaccine delivery to the urogenital mucosa for effective prophylaxis against urogenital infectious diseases. Further, it is desirable to have a rectally-administered vaccine for effective prophylaxis against rectal tract infections involving transmission through the anorectal tract.
The subject invention overcomes the above limitations and others, and teaches a suppository-based vaccine delivery system for prophylaxis against urogenital and anorectal tract infectious diseases, such as bacterial, protozoal, fungi, viral infections and the like, using fractionated, whole cell or purified protein, nucleic acid or lipid constituents, whether native, mutated, synthetic, cloned or recombinantly expressed, of urogenital/anorectal pathogens that stimulate the generation of humoral or cellular-mediated immune response.